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Functional Bone Replacement in Oral and Maxillofacial Surgery: Denition…
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7 Conclusion
Patient-specic implants fabricated by CAD/CAM technology from virtual models
can functionally replace mandibular bone defects. The surgeon should consider this
method along with the previously introduced techniques with successful results and
should choose the well treatment plan for each patient with the right rational.
Moreover, he/she should not forget the potential of the patient’s own body to regenerate itself. Indeed, the regenerative potential should be considered rst and, then,
move to replacement if this is not possible.
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Functional Bone Regeneration inOral
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andMaxillofacial Surgery: History,
Definition, andIndications
ParhamHazrati andArashKhojasteh
1 Introduction
Selection of the best set of techniques and materials to reconstruct maxillofacial
defects has remained somewhat challenging [1]. Application of autogenous bone is
considered as the gold-standard treatment with high success rates. However, modalities, such as patient discomfort, donor site morbidity, immune rejection, disease
transmission, unpredictable resorption rates, limited availability, and requiring
complicated surgical methods and prolonged hospitalization periods, can limit
application of bone grafting treatment [2]. To avoid the above disadvantages, tissue
engineering strategies, including application of cells and biomaterials, have gained
substantial attention [3–5]. This has resulted in an ongoing search for alternative
treatment choices [6–8].
Various biomaterials have been proposed in this regard. Allografts, as one of the
most commonly used ones, do not meet the requirements of osteoinductive signals
and vascularity [9]. The limited availability of these grafts is becoming an increasingly important problem as the demand for reconstructive strategies grows, in addition to other concerns, such as immune responses and infection transmission
[10–12].
Integration of computer-aided designing and manufacturing (CAD-CAM) technologies and the reconstructive maxillofacial eld has allowed individualized and
patient-specic application of bone tissue-engineered implants (i.e., functional
bone regeneration). This has allowed development of scaffolds in complete
P. Hazrati
School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
A. Khojasteh (*)
Department of Oral and Maxillofacial Surgery, Shahid Beheshti University of Medical
Sciences, Tehran, Iran
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023
A. Khojasteh et al. (eds.), Emerging Technologies in Oral and Maxillofacial
Surgery, https://doi.org/10.1007/978-981-19-8602-4_8
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accordance with defects topography and patient and implantation conditions [13–
15]. Thus, tissue engineering-based repair of the bony defects with the help of CAD/
CAM is thought to be a superior option, since the regeneration process may employ
the patient’s native tissue, and some constraints of conventional methods could be
overcome [16, 17].
It is vital to engineer bone regeneration in a way that allows the materials to
endure the earliest stages of healing and implantation in order to create a substitute.
This typically means that the regular cellular, biochemical, and biomechanical
obstacles must be overcome in a specic site as well as that bone must form quite
rapidly [18, 19].
This chapter discusses the underlying biological and functional background of
bone tissue engineering, essential points of designing and manufacturing scaffolds,
and clinical procedures of functional bone regeneration. In addition, clinical cases
of maxillofacial bone regeneration are presented.
P. Hazrati and A. Khojasteh
2 Definition
Using tissue engineering techniques for bone repair and regeneration, researchers
are attempting to stimulate new bone formation by the application of a synergistic
mixture of growth factors and cells in conjunction with a biomaterial scaffold [20].
Functional bone regeneration reects this regenerative thinking, where a bioengineered patient-specic implant is placed in the defective area to be gradually
degraded and replaced by new bone to restore function and esthetics. In contrast to
functional bone replacement or bone contouring, this approach will not leave a synthetic substrate in the body, and parallel to deposition of new bone, the grafted scaffold degenerates.
3 Functional andBiological Considerations
To achieve bone regeneration, functional and biological aspects must be thoroughly
considered and precisely employed in designing the treatment procedure. Longterm survival and regulated cell proliferation are required to establish tissue homeostasis in the freshly created bone [21]. Proliferation of cells should conform to a
balanced course; scaffold’s viability may be affected by inadequate proliferation,
while excessive proliferation might result in hyperplasia and apoptosis. The scaffold’s architecture should be well-structured, with proper porosity and interconnectivity of pores, mechanical properties, and degradation kinetics [22].
3.1 Porosity
Early in the process of bone regeneration, bone formation occurs near the perimeter
of scaffolds, with a negative gradient in mineralization occurring in the inner
Functional Bone Regeneration in Oral and Maxillofacial Surgery: History, Denition…
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sections of the scaffolds. When it comes to the continuous ingrowth of bone tissue,
interconnected porosity is of great importance, because it allows nutrients and bioactive molecules to transfer to the interior regions of the scaffold to aid cell proliferation, vascularization, and waste material disposal [23, 24]. Pore size of the
scaffold should be between 100 and 500μm in order to guide mesenchymal stem
cells’ migration, proliferation, and differentiation, provide oxygen and nutrients,
and promote diffusion of the bioagents causing bone formation in inner layers [25–
30]. Pore size below 100μm promotes chondrogenesis and eventual ossication,
while pore size over 100 μm induces direct ossication, but only up to a size
(approximately 500μm), where the scaffold’s durability is not compromised [31].
Generally, higher porosity leads to faster biodegradation [32]. Very small pore size
obstructs the bone ingrowth and evokes a foreign body reaction [28]. It has been
shown that scaffolds with pore size greater than 300μm promote increased bone
growth and vascularization [31, 33].
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3.2 Mechanical Properties
The mechanical characteristics should be like those of natural bone. Mechanical
strength is more important when considering restoring load-bearing or critical-sized
defects [34–36]. Mechanical strength is determined by the scaffold’s chemical composition, size, form, surface modication, and porosity [37]. Unfortunately, most of
the scaffold materials fail to properly imitate the physical characteristics of native
bone, such as elastic modulus. The elastic modulus of the condyle and the mandibular body are 120–450MPa and 112–910MPa, respectively [38]. In comparison, the
elastic modulus of most scaffolds fabricated via three-dimensional (3D) printing
ranges between 10 and 100MPa, which is much lower than the natural bone [37].
This may be the main obstacle to FBR application in load-bearing areas. The elastic
modulus in 3D printed scaffolds increases as the quantity of ceramic increases, as
well as when the porosity is reduced [39].
External surface topography of the scaffold should be rough enough to promote
surface ground for cell adhesion and proliferation while also tightly consolidating
with adjacent natural bone [25, 26, 40–43].
Furthermore, since brous tissue invasion is the primary cause of scaffold failure, the exterior surface should function as a barrier [28, 44, 45]. Covering the scaffold with a membrane is another way to prevent brous tissue invasion [26, 46, 47].
The biomaterial’s swelling and shrinking may harm the scaffold’s success, causing contamination and inammation at defect borders, as well as immune system
response.
3.3 Degradation
Degradation of the scaffold must follow a predictable and controllable rate. An ideal
scaffold’s degradation rate should follow the corresponding cells’ capability to
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P. Hazrati and A. Khojasteh
resorb the biomaterial and replace it with their own produced ECM.Optimal regenerative outcomes are achieved using biocompatible scaffolds with a degradation rate
analogous to new bone formation [48]. In this process, cells release proteases and
eventually produce ECM proteins dening the new tissue [21]. Biodegradation,
whether via a cell-mediated process or chemical dissolution, is critical for ensuring
stable healing and scaffold replacement with new bone that leaves no residual synthetic material [23]. Materials utilized in bone regeneration must be absorbed gradually, allowing the newly created tissue to take its place. Indeed, the delayed
degradation of the scaffolds may result in dehiscence as well as microbial contamination of the environment [37]. However, it has been reported that scaffold remnants could be traced in histological sections of functional regenerated bone even
after a long time (Fig.1) [49].
The kinetics of degradation and the mechanical characteristics of the material are
inextricably linked. Lower mechanical strength is followed by a faster degradation
pace [50, 51]. The high degradation rate promotes rapid bone turnover, prevents
inammation, and guards against bro gingival dehiscence and invasion [51]. As
mentioned before, scaffolds with higher porosity degrade faster [32]. It is mentioned that the scaffolds which are not fully degraded may be misinterpreted as new
bone [13].
Controlling degradation by-products is particularly difcult; the entire process
should be harmless, and degradation products should metabolize quickly without
posing a risk to cell survival and function [37].
a b
Fig. 1 A biopsy sample of the maxillary buccal plate with 23% biphasic calcium phosphate (BCP)
composed of HA and β-TCP and 57% regenerated bone after 7years. (a) Micro-CT image of
regenerated bone. Pink phase, B bone, white phase, Sc scaffold. (b) Light microscopic ground section of the specimen. B bone, MS marrow space, P biomaterial particle, CT connective tissue [49]
Functional Bone Regeneration in Oral and Maxillofacial Surgery: History, Denition…
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Neovascularized Bone
Graft
Localized
Bone Defects
Functional Bone
Regeneration
In-Situ Bone Regeneration
Free Flap
Success Rate Based on the
Defect Classification:
A>B>C , I>II>III
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Segmental Resection
Bone Defects
Extensive
Bone Defects
Composite Defect
Marginal Resection
Titanium Plate
In-Situ Bone regeneration
Free Flap
FBR
Free Flap
Pedicle Graft
Fig. 2 Decision planning tree to choose the proper patient for bone regeneration treatments based
on the defect size (i.e., whether it is greater than 6cm) and defect characteristics. Application of
regenerative material in combination with autogenous bone is not considered in the diagram.
Functional bone regeneration refers to using regenerative method without harvesting autogenous
bone from the patient. The classication that is mentioned for localized bone defects is based on
Khojasteh etal. [52]. FBR functional bone regeneration
4 Indications
Decision-making about whether a patient is a proper candidate for bone regeneration
therapy or not is a considerable challenging preliminary step. The clinical judgment
of surgeon should be based on the patient’s and defective site’s risk factors (Fig.2).
Cautions must be taken since patients who underwent radiotherapy treatments or
have continuity bone defects are not good candidates for bone regeneration treatments, and more studies are required to determine the treatment success in them.
5 Risk Factors
5.1 Recipient Site Characteristics
Recipient site morphology and characteristics remarkably inuence the outcome of
regenerative procedures [52]. The recipient site’s potential for new bone formation
impacts success of regenerative therapy; for instance, healing and regeneration are
delayed and scant in a defective site with diminished vascularity or cellularity [53].
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Additionally, the dimension of the defect should not be higher than the penetration ability of cells and vessels [54]. In large grafts, the vascularization could not be
completed, jeopardizing regeneration and healing processes [55]. Most trials performed on humans have reported that defects wider than 12 mm in height and
10mm in width were not considered to respond well to this modality and hence
were not treated [15, 56, 57]. However, defects as large as 30mm×20mm have
been treated with tissue-engineered scaffolds in animal models [58–61].
The shape of the defect is critical to the effectiveness of bone in-growth; for
example, it is better to have a wide surface connection with native bone and, as a
result, closeness to osteoprogenitor cells and greater surface area for providing vascularization [62]. It has been mentioned in the literature that broad alveolar ridges
respond better to regenerative therapies compared to narrower ones [63]. In defects
surrounded by fewer numbers of bony walls, the possibility of ap or membrane
collapse is higher, and it can blemish the initial blood clot formed in the regenerative space [64]. Scaffolds that only connect to the natural bone by one narrow wall
have a higher risk of failure [65, 66].
In addition to the morphological and dimensional considerations, anatomical site
of the defect might also play a crucial role in osteogenesis. Anterior and posterior
portions of maxilla or mandible contain divergent quality, so they might illustrate
different regenerative potency [53].
P. Hazrati and A. Khojasteh
5.2 Vascularity
Simultaneous development of angiogenesis and osteogenesis has a determinant role
in both physiological bone repair after injury and successful bone regeneration [62].
Bone regeneration necessitates copious angiogenesis [67]; nevertheless, despite
recent advances in tissue-engineered approaches, making it a competent option,
bone regeneration is still facing the problem of low or insufcient vascularity [8].
Naturally, bone is an exceedingly vascularized and innervated tissue [68]. Blood
vessels of bone have many essential roles in remodeling, development, and growth
[69]. Vascular endothelial cells inuence the dynamic balance of osteogenesis and
osteoclastogenesis through various signaling pathways. The bioactive scaffold utilized during functional bone regeneration should allow blood vessels to colonize, in
addition to being biocompatible [69].
During bone repair and regeneration, bone marrow mesenchymal stem cells
(BMSCs), residing in the bone marrow that are precursors of osteoblasts, differentiate and migrate to the surface to engage in regeneration process. This process is
utterly related to invasion of blood vessels to the defective site [70]. Blood vessels
provide oxygen and nutrients to newly formed osteoblasts and dispose waste metabolites, by creating a local circulation, and also directly promote new bone formation
[71]. Revascularization directly affects bone regeneration by osteogenic cell condensation and differentiation [72]. The rst step in angiogenesis is activation of host
vasculature by angiogenic growth factors, such as vascular endothelial growth factor (VEGF) or basic broblast growth factor (bFGF) [73]. Afterward, existing
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125
vessels begin to germinate into the scaffold [74, 75]. The developing vessels continue to grow into the scaffold and create an interconnected microvascular network [76].
There could be different strategies to secure the scaffold’s blood supply and relative regenerated bone (Fig.3) [8]. The classic vascularization strategy relies on the
adg
be h
cf i
Fig. 3 Overview of different strategies for vascularization; the left column (a–c) represents a graft
that is entirely dependent on angiogenesis from the host; the middle column (d–f) illustrates a graft
with preformed vasculature; and the right column (g–i) demonstrates a scaffold containing microvascular fragments [8]
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